From acute to chronic inflammatory disease—where is the boundary?
An acute infectious disease can be self-limiting and involve an innate immune response of 2 to 3 days; the subsequent phase of the adaptive immune response can last approximately 3 to 4 weeks. Similarly, many transient inflammatory episodes include a healing phase that involves adaptive immune responses (Table ). The typical germinal center reaction of affinity maturation of B cells occurs for 3 to 4 weeks from the beginning to end [22
]. The accompanying proliferative T cell response undergoes a similar time course [24
]. The response of the adaptive immune system with a maximum of proliferation until days 12 to 14 and subsequent contraction until days 21 to 28 is surprisingly constant in various acute infectious diseases [24
]. Upon generation of immunological memory, the entire process can be markedly shortened, and this was a selection advantage [24
]. An important question concerns the dynamics of this response: why do the increase and decrease of the adaptive immune response not last longer?
Acute self-limiting infectious diseases can be very energy consuming although, in the presence of disease-induced sickness behavior and related anorexia (Table ) [9
], intake of energy-rich substrates can be significantly inhibited. To explain these seemingly disparate observations, it can be proposed that sickness behavior represents an element of an adaptive program that has been positively selected for transient immune and inflammatory reactions to limit energy utilization for such activities as foraging and courtship behavior [8
]. In such a situation, the immune response can not last forever because energy stores run empty.
Furthermore, sickness behavior can restrain activity and, for example, confine the affected individual to a safe place to keep away predators [8
]. In considering energy stores available during these responses, it is important to note that storage occurs primarily in fat tissue (12 kg of triglycerides in the body of a contemporary person, 500,000 kJ), as well as in the liver (150 g glycogen, 2.500 kJ) or muscles (300 g glycogen, 5,000 kJ; 6–7 kg muscle protein, 50,000 kJ) [11
Under conditions of sickness behavior and anorexia without uptake of energy-rich substrates but an increased sickness-related metabolic rate (Tables and ), the total amount of stored energy would only last for 19 to 43 days in females and 28 to 41 days in males (Table ). The number is relatively similar for domestic fowl which have an evolutionary distance to Homo sapiens of 300 million years (Table ). In other words, an acute consuming infectious disease that uses all energy stores can only last until the stores are empty, say 19 to 43 days. Thus, the evolutionarily positively selected increase and decrease of an adaptive immune response must fit into this prespecified time frame. Due to the physical restrictions of energy storage under natural paleolithic conditions, an acute infectious disease may not last much longer than 3 to 6 weeks. It can be hypothesized that energy considerations can help explain the relatively constant time course of an adaptive immune response in the context of acute infection.
Total consumption time in human evolution
If an acute inflammatory response lasted longer than the time point at which energy stores were exhausted, the affected person would probably have died due to inanition and starvation, preventing transfer of genes to any offspring. If, however, an immune response lasted for a shorter period, the affected person could survive and be able to transfer favorable genes to offspring. These considerations thus suggest that the time point of total energy consumption marks the upper threshold of an acute disease period for which genes, signaling pathways, and networks can be subject to positive selection. But what happens to the survival of the individual after this physical threshold of total energy consumption?
It can be hypothesized that networks for more persistent inflammatory diseases do not exist because they have not undergone the pressure of positive selection. If a disease is progressive and longstanding (e.g., autoimmunity) and therapies are available to stop lethal emaciation (i.e., immunosuppression), a chronic phase can develop. For the chronic phase of such immune-mediated diseases, the organism would lack positively selected genes, signaling pathways, and networks to be able to stop the chronic disease in a coordinated fashion. Thus, sickness behavior and energy disturbance would remain and impair the function of the individual. It becomes a perpetuating factor (Table ).
The framework of evolutionary biology and neuroendocrine immune energy regulation thus defines the point of transition from acute disease to chronic disease as the time point of complete energy consumption (19–43 days). In this regard, the point can represent a range in time because the consumption curve depends on stored energy reserves (Table ).
Inflammation, energy demand, and water retention—an evolutionary link between inflammation and hypertension
Acute inflammatory episodes require abundant energy and are often accompanied by local and systemic water loss (Table ). Local water loss is particularly important when the inflamed tissue has an exposed surface area such as the skin or to inner surfaces of the gastrointestinal, respiratory, or urogenital tract. For example, water loss through skin wounds depends on the surface area and can amount to 0.35 ml/cm2
/day (area, 30
315 ml/day) [28
]. Another example of water loss relates to insensible perspiration. Under normal conditions in adults, insensible perspiration through skin and respiratory tract can reach 0.5 ml/kg/h (example, 80 kg and 24 h
960 ml/day) [29
]. During surgical intervention, which is a model of mild acute inflammatory activation, water loss by insensible perspiration can amount to 1 ml/kg/h (example, 80 kg and 24 h
1,820 ml/day) [29
]. These numbers show that loss of water can be quite high during acute inflammatory episodes.
Water loss during transient inflammatory episodes
In addition to physical loss of water via outer and inner surfaces, many metabolic reactions that degrade storage forms of energy-rich substrates need water for hydrolysis (Fig. ) [30
]. For example, the breakdown of one molecule of glucose from glycogen needs two molecules of water (Fig. , pink area in left upper corner); triglyceride breakdown needs three molecules of water for three molecules of free fatty acids (Fig. , pink and yellow area on the left side); and degradation of muscle protein needs particularly many molecules of water (Fig. , brown area in right upper corner) [31
]. If amino acids are completely degraded within the urea cycle in the liver, one molecule of water is needed for one molecule of amino acid (Fig. , pink area in the left upper corner).
Fig. 1 Water fluxes in the system (blue box) and inflamed tissue (orange box). Blue box it is demonstrated that liver cells (pink box) need water for degradation of glycogen, triglycerides, amino acids in the urea cycle, and for gluconeogenesis in the context (more ...)
Furthermore, the generation of the Cori cycle between the lactate-producing inflamed tissue and the glucose-producing liver [33
], involving gluconeogenesis, needs five molecules of water to reactivate one molecule of lactate (Fig. , red lines with arrows) [31
]. Finally, the operation of a proper adaptive immune response with proliferation of B cells and T cells and proliferation of innate immune cells (neutrophils, monocytes) in primary and secondary lymphoid organs needs enormous amounts of water (Fig. , green area in left lower corner) [31
]. The water loss described above is water loss in the system (liver, muscle, fat tissue, lymphoid organs, and others). It is not local water loss in inflamed tissue because here, in contrast, water is produced.
Water is formed when glucose, amino acids, and free fatty acids undergo degradation in the Krebs cycle and during oxidative phosphorylation; these processes occur in the mitochondria of activated cells in inflamed tissue (Fig. , orange area). Thus, important differences exist for water loss from the system and the generation of water from locally inflamed tissue. The amount of locally formed water can be large (Fig. , orange area), but usually water is lost rapidly in the environment of inflamed tissue via outer and inner surfaces (Table ).
To overcome systemic water loss during acute inflammatory episodes and events such as trauma, hemorrhage, and burns, a water retention system is activated. The key elements of this system are the sympathetic nervous system (SNS) that activates the renin–angiotensin–aldosterone pathway [34
], and the hypothalamic–pituitary–adrenal (HPA) axis with ACTH, aldosterone, and cortisol. ACTH can stimulate aldosterone as well as cortisol, which also has mineralocorticoid activity [35
]. It may not be a simple coincidence that the SNS and the HPA axis can redirect energy-rich substrates from energy stores to the activated immune system as well as serve as major water retention systems. In this context, it is important to recall that the acute adaptive response described by Selye in the 1940s was considered a “nonspecific” alarm reaction [36
]. Today we can say that Selye’s alarm reaction was not “nonspecific” but rather had important physiologic functions as both, a highly specific energy appeal reaction (as described earlier [9
]) as well as a specific water retention reaction.
The SNS and the HPA axis are supported by other alarm hormones such as vasopressin (which is lipolytic and water retentive), growth hormone (glucogenic, lipolytic, and water retentive), and insulin (lipogenic and water retentive). During transient inflammatory episodes, due to sickness behavior and anorexia, lipogenic insulin most probably plays a minor role because insulin secretion activated by the presence of carbohydrates would be downregulated. Thus, while sickness behavior may have antilipogenic consequences by suppressing insulin secretion, it can also be prolipolytic through activation of the SNS and the HPA axis. It leads to redirection of stored energy to the activated immune system.
These ideas can explain other activities of physiological mediators and provide insights in findings that, for example, water retention hormones such as angiotensin II have proinflammatory activities [37
]. Angiotensin II uses the important proinflammatory signaling cascade of NF-κB activation similar as TNF [38
]. Inhibition of the renin–angiotensin–aldosterone system by angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists exert anti-inflammatory effects as summarized elsewhere [39
]. In the setting of acute inflammatory episodes such as infectious disease, it is important that the energy appeal reaction and the water retention reaction support the proinflammatory process to eliminate the infectious agent. It can be hypothesized that the water retention hormone angiotensin II is immunomodulatory in this respect.
In conclusion, the water retention system shows important similarities to the energy provision system, with operation of the two interacting systems subject to positive selection in evolution to overcome serious, albeit non-life-threatening, transient inflammatory episodes (Table ). This possibility is supported by the proinflammatory activity of water retention hormones. It is therefore important to consider the role of the water retention system in settings of chronic inflammation such as may occur in aging as well as rheumatic and autoimmune diseases undergoing medical treatment (after entering the chronic phase).
Both the aging process and medically treated chronic inflammatory diseases are accompanied by mild inflammation, a state that one might call low-grade smoldering chronic inflammation [40
]. In these settings, circulating cytokine levels can be 5 to 10 times higher than normal (e.g., IL-6 from 2 pg/ml to 10–20 pg/ml), and the overall stimulus might be strong enough to induce a mild systemic water retention and energy appeal reaction (responses shown for low IL-6 serum concentrations in ref. [42
]). Since no positively selected programs exist for aging [44
] and chronic inflammatory diseases [8
], genes, signaling pathways, and networks that are operative in this setting are similar to those that determine acute episodes of inflammation (Table ).
Under conditions of local inflammation with exposed outer and inner surfaces, circulating cytokines from inflamed tissue activate the energy appeal and water retention reaction. Since the local inflammatory process leads to water loss over local surfaces, locally formed water—by degradation of energy-rich fuels in activated inflammatory cells (Fig. , orange area)—can be rapidly lost via the exposed surface (Fig. ). It can be hypothesized that, in the presence of local and systemic water loss, the water retention system will not induce hypertension under these acute inflammatory conditions.
Fig. 2 Water fluxes between the system and inflamed tissue with water loss in a transient acute inflammatory episode (a) and without water loss in chronic inflammation (b). a Water fluxes with water loss in acute inflammatory episodes. The inflamed tissue ( (more ...)
The situation of water retention might be very different depending on the setting and operation of different mechanisms of water loss. These mechanisms would include the following events which may be present during disease: local water loss through outer/inner surfaces (Table ), water loss due to systemic effects such as fever (Table ), recirculation of formed water from activated inflammatory cells; and cytokine-activated water retention and energy appeal reaction. Depending on the operation and extent of these mechanisms, systemic hypertension could result from the continuous activation of a water retention and energy appeal reaction but without the usual water loss (Fig. ).
Indeed, in aging and in chronic inflammatory diseases, both the SNS and the HPA axis are chronically activated [41
]. In addition, there are obvious signs of volume overload in chronic inflammatory diseases because serum levels of atrial natriuretic factor and NT-brain natriuretic factor are markedly increased in different diseases [49
]. NT-brain natriuretic factor decreased with TNF neutralization therapy but increased under therapy with volume retention—inducing glucocorticoids [49
The revised version of the theory predicts that the operation of these mechanisms will not depend on the site of inflammation and whether it occurs in arteries, kidneys, gastrointestinal tract, joints, or at various tissues with inflammatory cells. The key feature relates to the production of cytokines of inflammatory cells, their activation of the energy appeal and water retention reaction, and the extent of water loss via inner and outer surfaces. The magnitude of these changes would determine any detrimental effect on the induction of hypertension. Since prevalence of essential hypertension in adults is 22–32%, these theoretical considerations are highly clinically relevant.
As noted above, the energy appeal reaction and water retention reaction appear to be the result of selection in evolution for their role in transient inflammatory episodes. Induction of energy appeal reaction and water retention reaction provide a survival value if used for a short period of time. However, prolonged operation of these adaptive programs such as in chronic inflammatory diseases of today can in itself become pathogenic because there is no program to counteract continuous water retention and energy appeal reaction during long-term age-related inflammation and in chronic inflammatory diseases.